DESCRIPTION (Adapted from the abstract provided by the applicant): Several lines of evidence suggest that Huntington's disease (HD) and Parkinson's disease (PD) have defects in mitochondrial function that impair oxidative phosphorylation and play a key role in the mechanism of neuronal death. To date, however, there have been no direct measurements of cerebral oxygen to glucose metabolic ratios to demonstrate an in vivo defect in cerebral mitochondrial metabolism in these diseases. We will use positron emission tomography (PET) to measure in vivo regional cerebral oxygen metabolism (CMR02) and cerebral glucose metabolism (CMRglc) to test two primary hypotheses: 1) Patients with HD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 gene-positive pre-symptomatic patients with HD, 15 gene-positive patients with HD and definite motor signs and 30 age/gender-matched normal controls. 2) Patients with PD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 never-medicated, early PD patients and 15 age/gender-matched normal controls. In the same subjects, we also will test two secondary hypotheses: 3) Regions vulnerable to pathologic insult have larger magnitude or selective defects in cerebral mitochodrial metabolism - caudate and putamen in HD and substantia nigra and putamen in PD. 4) In PD and HD, the degree of dysfunction in platelet electron transport complex function measured in vitro correlates with the degree of abnormal cerebral mitochondrial metabolism measured in vivo. At this time it is not clear how the abnormalities in electron transport chain activity measured in vitro in these two diseases correspond to cerebral mitochondrial metabolism in vivo. Direct in vivo regional PET measurements of CMR02 and CMRglc will allow us to demonstrate the extent and magnitude of mitochondrial dysfunction in vivo. Establishing the existence of cerebral mitochondrial dysfunction early in the course of these diseases will not only provide insights into the pathogenesis, but it will provide a measurable biological abnormality that can be monitored to determine the effect of treatments aimed at slowing or halting the progression of neuronal loss. The opportunity to determine the relation between platelet mitochondrial function and cerebral mitochondrial metabolism in patients with PD and HD is uniquely important. If such a relationship can be established in untreated patients in this study, then we would pursue further studies to determine the effects on cerebral mitochondrial metabolism of agents that alter platelet mitochondrial function. If such studies yield consistent results, they will establish the basis for the utilization of platelet rnitochondrial function assays to monitor cerebral mitochondrial metabolism.